1. Field of the Invention
This invention relates generally to the fields of cancer biology and endocrinology and, more specifically, to biological activities of RIZ polypeptides.
2. Background Information
Post-translational addition of methyl groups to the amino-terminal tails of histone proteins is catalyzed by a family of proteins known as histone methyltransferases (HMTs). Histone site-specific methylation is associated with a variety of fundamental cellular processes, including transcriptional regulation, epigenetic silencing and heterochromatin formation. Loss of HMT function is expected to directly contribute to the de-differentiation and genomic instability that are characteristic of cancer.
Further implicating HMTs in cancer, it has been shown that a deficiency in dietary methionine or folate causes cancer. Dietary methionine and folate in turn regulate the cellular levels of S-adenosylmethionine (SAM), which is used as a methyl group donor by methyltransferases.) Additionally, several independent lines of investigation have revealed that alterations in the methionine metabolic pathway, which can lead to a deficiency in SAM and/or an increase in the methyltransferase inhibitor S-adenosylhomocysteine (SAH), are associated with cancer.
Thus, there exists a need to identify proteins with histone methyltransferase activity, determine their substrates and regulators, and identify compounds that modulate their activity. In particular, there exists a need to identify histone methyltransferase activity within proteins already recognized to play critical roles in regulating cell proliferation. Compounds that modulate the HMT activity of such proteins are expected to be useful as therapeutics to regulate cell growth.
The steroid hormone progesterone is a critical component of the female reproductive cycle and is required to maintain pregnancy. The molecular target of progesterone is the intracellular progesterone receptor. Upon binding to progesterone, the progesterone receptor translocates to the nucleus where it binds as a transcription factor to DNA transcriptional elements present in progesterone-regulated genes.
Ligands to the progesterone receptor play an important role in female reproductive medicine and cancers. For example, progesterone and its synthetic analogs are useful in birth control formulations, in treating endometriosis and in maintaining pregnancy. Antagonists to progesterone are useful in treating chronic disorders such as certain forms of hormone dependent cancer of the breast, ovaries and endometrium (the lining of the uterus) and in treating uterine fibroids. Progesterone antagonists are also useful in combination with other drugs for terminanting early stage pregnancies.
Compounds that modulate progesterone receptor activity are thus expected to be useful in reproductive applications and for treating malignant disorders. However, suitable high-throughput assays for identifying such compounds are currently lacking, in part due to a lack of understanding of physiologically relevant interactions of the progesterone receptor with cellular molecules. Thus, there exists a need for improved methods to screen for compounds that modulate progesterone receptor activity.
The steroid hormone estrogen directly and indirectly promotes the proliferation of tissues expressing estrogen receptors. Endocrine therapy to reduce the proliferative effects of estrogens, including therapy with selective estrogen receptor modulators (SERMs) such as tamoxifen, is currently the preferred first-line therapy in patients with estrogen receptor positive (ER+) tumors. However, a significant portion of patients with ER+ tumors do not respond to endocrine therapy. In these patients, alternative therapies are warranted in order to improve the odds of survival. Currently, there is no satisfactory method of predicting which ER+ tumors will respond to endocrine therapy.
Thus, there exists a need to identify molecules that correlate with loss of estrogen responsiveness in ER+ tumors, in order to more accurately determine which individuals are more or less likely to respond to endocrine therapy. Using such a correlation, an individualized course of treatment with an improved likelihood of success can be chosen.
The present invention satisfies these needs, and provides related advantages as well.